research article multiple sclerosis state of the art...

Research ArticleMultiple Sclerosis State of the Art (SMART): A Qualitativeand Quantitative Analysis of Therapy’s Adherence, HospitalReliability’s Perception, and Services Provided Quality

G. Di Battista,1 A. Bertolotto,2 C. Gasperini,3 A. Ghezzi,4 D. Maimone,5 and C. Solaro6

1 Neurology Unit, Department of Neuroscience and Sense Organs, A.C.O San Filippo Neri, Via G. Martinotti 20, 00135 Rome, Italy2 Clinical Neurobiology Unit, Regional Referring Multiple Sclerosis Centre (CReSM), University Hospital San Luigi Gonzaga,Orbassano, 10043 Turin, Italy

3 Department of Neurology, A.O. San Camillo Forlanini Hospital, Circonvallazione Gianicolense 87, 00152 Rome, Italy4Multiple Sclerosis Study Centre, Gallarate Hospital, Via Pastori 4, 21013 Gallarate, Italy5 Neurology Unit, A.O. Garibaldi Nesima, Piazza Santa Maria Del Gesu 5, 95122 Catania, Catania, Italy6Neurology Unit, Department Head and Neck, ASL3 Genovese, Via D. Oliva 22, 16154 Genoa, Italy

Correspondence should be addressed to G. Di Battista; [email protected]

Received 29 December 2013; Revised 18 June 2014; Accepted 23 June 2014; Published 26 August 2014

Academic Editor: Wolfgang Bruck

Copyright © 2014 G. Di Battista et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The purpose of this study was to assess the adherence to therapy in patients with relapsing remitting multiple sclerosis (RR-MS)and to analyze the possible influence of factors such as hospital care and patients socioeconomic status. Two hundred eighty-fivepatients with RR-MS according to Mc Donald’s criteria and naıve disease-modifying drugs (DMDs) naıve were enrolled. Two self-administered questionnaires addressing the management of patients at therapy prescription and the personal perception of thedaily life changes caused by DMDs were administered at months 3 and 12. Full adherence, considered as correct use of the therapyprescribed, was observed in a very high percentage of subjects (97.3% and 93.9% at 3 and 12 months). The main cause for reducedadherence was single dose forgetfulness, followed by anxiety, pain at the injection site, and tiredness of “doing all injections.” Nursesand neurologists of MS Center were identified as the major resource in coping with the disease at 3 and 12 months by patients. Theneurologist was the health professional involved in MS management in 95% of cases and the nurse appeared to play a central rolein patient training and drug administration management (50.3%).

1. Background and Objective

Adherence to prescribed treatment in chronic disease is a crit-ical factor for a successful therapeutic response; however, inconditions like multiple sclerosis (MS), where the treatmentis mainly preventive, it may be inadequate. The reasons forpoor adherencemay be related to lack of perception of imme-diate benefits and to the inconvenience and discomfort ofinjectable treatment.

The general definition of treatment adherence [1] includestreatment persistence and compliance. Treatment persistencerefers to a patient’s enduring motivation to continue a giventreatment and it can be measured by the time from initiationto discontinuation of therapy. In theWorld Health Organiza-tion [2] project for long-term therapy, adherence (treatment

compliance, synonym: adherence) has been defined as “theextent to which a person’s behaviour—taking medication,following a diet, and/or executing lifestyles changes—corre-sponds to agreed recommendations from a healthcare pro-vider” [3] and in patients with MS or other chronicle illnessmeans the extent to which a patient acts in accordance withthe prescribed interval and dosing of a drug regimen. Thecompliance is measured over a period of time and reported asa percentage.

There are not many studies on adherence inMS andmostof them mainly focus on discontinuation of therapy [4–6]rather than adherence intended as proper use of therapyaccording to prescription (number of missing doses) [7].Thereason for failing in assessing adherence may derive from tothe difficulty in monitoring the data [8].

Hindawi Publishing CorporationMultiple Sclerosis InternationalVolume 2014, Article ID 752318, 9 pageshttp://dx.doi.org/10.1155/2014/752318

2 Multiple Sclerosis International

Noncompliance is frequent among patients with MStaking disease-modifying drugs (DMDs) because they some-times forget a dose or deliberately withhold it. In the GlobalAdherence Project, Devonshire and colleagues [9] found thatthe most common reason for noncompliance among patientswith MS was forgetting to inject (50%). Anecdotally, patientsfrequently cite other reasons for noncompliance, such asfatigue, needing a break, or adverse events.

There are several causes that may lead to suspension orirregular management of therapy including occurrence ofside effects which worsen the quality of life, perceptions ofineffective or unnecessary therapy, forgetfulness, and incor-rect understanding of the drug. Furthermore, subjects treatedin clinical practice may receive a less intensive follow-up byspecialist practitioners than those included in clinical trials,and this can further interfere negatively in adherence and effi-cacy [10–12]. Mohr et al. [13] reported also that the therapy iscontinued regularly in 86% of patients with depression iftreated with antidepressants, whereas in untreated depressedpatients adherence falls to 38%.

The purpose of this study was to assess the treatmentadherence to DMDs, intended as adherence to prescribednumber of doses and doses voluntarily not taken withoutpermission, in patientswith relapsing remittingMS (RR-MS).The study also included the analysis of possible factors suchas hospital care and patients socioeconomic status.

2. Materials and Methods

SMART (State of the Art Multiple Sclerosis) is a prospec-tive observational multicentric study using self-administeredquestionnaires conducted in 34 MS centers at public hos-pitals, distributed throughout the national territory andauthorized to prescribe DMDs for MS. The questionnairesincluded the following items andwere administered 3monthsand 1 year after drug prescription.

Items Reported in the Questionnaires. Demographic and soci-oeconomic data include

(i) sex;(ii) age (years);(iii) what your qualification is;(iv) what your occupation is;(v) who currently lives.

MS Diagnosis and management include

(i) age at diagnosis of MS (only 3 months);(ii) whether you are currently followed up at the center

where you were first diagnosed;(iii) which health care professional regularly sees your

condition;(iv) how often on average sees your neurologist;(v) how often medium sees your neurologist;(vi) how long you are engaged in the consultation with a

neurologist (min);

(vii) how often you contact your nurse;(viii) how long you engaged in a visit with the nurse (min).

Which of the following factors is important in the choiceof therapy for the MS?

(i) The drug’s mechanism of action;(ii) The drug reduces the relapses;(iii) The drug slows the progression of the disease;(iv) The drug produces fewer antibodies;(v) The drug is well known;(vi) The drug has few side effects;(vii) The drug improves my MRI;(viii) The support of a nurse to give injections;(ix) The information support provided by the company

that makes the drug;(x) The mode of administration (im/sc);(xi) The ability to self-administer the injections;(xii) The availability of an autoinjector;(xiii) How many times a week I should take the drug;(xiv) The independence that a treatment can give.

Who prepared you for taking the medication?

(i) Was I already aware of these treatments forMS? (only3 months).

(ii) Was I prepared to give myself injections? (only 3months).

(iii) By whom was I prepared? (only 3 months).(iv) Who administers the injections? (only 3 months).(v) What is themain resource in dealingwith the disease?

Therapy includes the following.

(i) Who decided the treatment? (only 3 months).

Judgment on therapy for MS includes the following.

(i) Do you feel satisfied with the current treatment?(ii) What do you think of the current therapy?(iii) Do you believe the therapy can slow the progression

of the disease?(iv) Please indicate how much you agree or disagree with

what is written below.(v) What are the side effects of treatment?(vi) My symptoms improved a year ago (only 12 months).(vii) How many times a week according to your neurolo-

gist’s prescription do you make the injections?(viii) How often do you apply the regimen prescribed by

your neurologist?(ix) Would you tell your neurologist that you did not

follow perfectly what he prescribed?

Multiple Sclerosis International 3

(x) Howmany injections have you forgotten by choice orby accident in the last 4 weeks?

(xi) How many injections have you missed?(xii) Have you decided to change the dose to inject in the

last 4 weeks?

Eligible patients were identified at the time of first therapyprescription. Inclusion criteria were age older than 18 years,being diagnosed with RR-MS according to the 2005 revisedMc Donald’s criteria [14], and being naıve to therapy withDMDs at the time of study entry. Furthermore, to participatein the study, patients should agree to start therapy, signinformed consent, and fill out the first diary to 3 months.

After having signed the informed consent, each patientreceived andfilled the questionnaires. Amedical form includ-ing demographic and clinical data was also filled out atenrollment and updated during the follow up.

All patients began treatment immediately after thescreening with EMA-approved DMDs (IM interferon beta-1a[Avonex, Biogen Idec], interferon beta-1b [Betaferon, Bayer],glatiramer acetate [Copaxone, Teva Neuroscience], and SCinterferon beta-1a [Rebif, Merck Serono]).

Follow-up duration was 12 months. Two self-admini-stered questionnaires at 3 and 12 months were used to assessadherence to therapy. Furthermore, the first questionnaireevaluated also the management of patients at therapy pre-scription, whereas the second aimed also to verify thepersonal perception of the daily life changes caused byDMDs(see the items reported in the questionnaires).

The primary endpoint was the assessment of the treat-ment adherence considered as acceptance of the prescriptionmade by the physician and analysis of the causes. Thesecondary endpoint was the identification of the reasons thatled to the acceptance, or modification of therapy.

The study was approved by local ethics committee at eachcenter and was conducted according to GCP rules.

3. Statistical Analysis

Data were presented as mean ± standard deviation (SD),median, or percent, where appropriate. Statistics were per-formed by analysis of variance (ANOVA) for continuous vari-ables with normal distribution and by Kruskall-Wallis non-parametric test for discrete variables. Variables of nominaltype were analyzed by 𝜒2 test and the McNemar test in orderto compare the observed frequencies at 3 and 12 months.Theduration of treatment was evaluated according to Kaplan-Meier survival curve and Cox model [15–17].

4. Results

4.1. Patients Characteristics (Table 1). Of the 285 patientsincluded, 198 were females (69.5%); themean age was 36 (10.9SD, Min 16.6, Median 35.4, Max 61.6); and the mean lengthof education was 12.29 years (SD 3.04, Min 5.0, Median 13.0,Max 20.0). The mean age at MS onset was 31.22 (SD 9.39)and the mean time from onset to diagnosis was 2 years. Onehundred sixty out of 263 were working in full or partial time

(men 72.2%, women 56.0% reaching 74.5% by adding thehousewives), whereas the remaining patients were students(9.5%), retired (4.2%), or unemployed (12.5%). There was nosignificant loss of employment at 3 and 12 months (McNemartest).

Most of the patients lived at home with their parents orspouse and only 7% lived alone (F 8.0%, M 5.1%).

The mean interval from diagnosis to therapy onset was1.94 years (SD 3.9) and the EDSS score at study entry wasbetween 0 and 3.5 in 95% and between 4 and 5.5 in theremaining 5% of patients.

Follow-up data were available for 262 patients after 3months and for 248 patients after 12 months. Thirteenpatients discontinued therapy between the first and the sec-ond questionnaire and one was lost to follow-up. Causes fortreatment discontinuation were ongoing or planned preg-nancy (4 cases), refusal of therapy (1 case), comorbidities notrelated to therapy (2 cases), and side effects due to therapy(depression, elevation of transaminases, and allergy) (1 case).

4.2. Therapy’s Adherence. A very high percentage of subjects“always try to follow the schedule prescribed” (255/262 pts,97.3%, at 3 months, and 233/248 pts, 93.9%, and at 12 months;226 patients (96.6%) out of 234 at both 3 and 12 monthsconfirmed the same response) (Table 6).

The main causes of lack of adherence (Table 7) wereforgetfulness of a single dose (14.5% and 17.4% at 3 and 12months), followed by anxiety generated by injection (12.0%and 13.0% at 3 months and 12 months), pain at the injectionsite (10.3% at 3months and 10.4% at 12months), and tirednessof “doing all injections” (9.4% at 3 months and 7.8% at 12months).

When asked whether they had missed, by choice oraccident, an injection in the past 4 weeks, patients gavenegative response in 85.9% and 80.2% of cases at 3 and 12months, respectively (Table 9). The adherence data are con-firmed in Table 10 with 97.2% of patients at 3 months and95.8% at 12 months stating not to have changed, in the last4 weeks, the dose prescribed.

Patients concealed their lack of adherence only in 15.3% ofcases at 3 months and in 9.7% of cases at 12 months (Table 8).Women responded more sincerely then man, at 3-monthquestionnaires, with a statistically significant difference in the𝜒2 test with continuity correction (23.7% of men say “no”

compared to 12.2% of women, 𝑃 = 0.03). A 12-month (“no” =9.7% ) versus 3-month (“no” = 15.3%) statistically significantdifference (𝑃 = 0.04) was also detectable with McNemar testwith continuity correction.

People forgetting or missing the injections also indicatesthe number of skipped injections: 35 missing doses (mean2.9± 4.1) per person atmonth 3; 37missing doses (mean 2.4±1.9) per person at month 12.

4.3. Leading Figures in the Management of the Disease. Morethan 80% of patients affirmed to be followed up at the centerwhere they were diagnosed with MS both at 3- and 12-monthevaluation (82% and 87%, resp.), with no gender differences(McNemar test with continuity correction). The neurologist


Table 1: Demographic data.

Sex Females 198 (69.5%) Males 86 (30.2%)Age Mean 36.1 (10.9 SD) Min 16.6—max 61.6

Education

Years 12.3 (3.0 SD)Lower school 3 months: 69 (26.3%) 12 months: 61 (24.6%)High school 3 months: 136 (51.9%) 12 months: 134 (54.0%)Graduate 3 months: 42 (16.3%) 12 months: 42 (16.5%)Other/ND 3 months: 15 (5.7%) 12 months: 12 (4.8%)

Work

Full or partial time M 72.2% F 56.0%Housewives F 13.5%Student M 5.1% F 11.4%Retired M 8.9% F 2.2%

Unemployed M 13.9% F 12.0%

Social statusAlone M 5.1% F 8.0%

With parents M 34.2% F 28.3%With others M 60.7% F 63.7%

Age at MS onset 31.2 (9.4 SD) Min 9.0—max 57.5Age at diagnosis 34.0 (9.8 SD) Min 9.7—max 58.1Time from diagnosis to therapy starting Years 1.9 (3.9 SD)

was the health professional involved in MS management in95% of cases (Table 2).

Neurologists and nurses of MS Center were identified bythe patients as the major resource in coping with the diseaseat 3 months by the patients (for 67.2% and 63.7% of patients,resp.); these data were confirmed at 12 months (for 62.5% and61.7% of patients, resp.) (Table 3). However, patients believedthat the family is the most important resource in coping withthe disease burden (81.7% at 3 months, 82.3% at 12 months)(Table 3).

The nurse was identified as the central player in patienttraining and drug administration management (50.3%) at 3months followed by the neurologist.

4.4. Shared Decision Making and Involvement with ReferralCenter. The relationship between the people involved in thedecision of initiating MS treatment is reported in Table 4. Inmost cases, the neurologist played a crucial role in makingthe decision to start DMD therapy, although patients often,more or less actively, participated to this choice (totally 76%ofcases). In a very few cases (3/255 pts), patients decidedindependently from their neurologist and 58/255 patients leftthe decision to the neurologist.

4.5. Factors Influencing the Treatment Choice. The factorsinfluencing the choice of treatment (Table 5) can be clusteredin two groups: the drug therapeutic properties and the effectsDMDs on daily life. The belief that therapy can preventrelapses or slow the progression of the disease is importantfor 64.1% and 67.2% of patients, respectively, at 3 months andfor 64.3% and 65.6% of patients, respectively, at 12 months.

The presence of side effects is important in 51.4% at 3months and 44.8% at 12 months. Perceived lack of efficacyand side effects are usually considered the main responsiblefactors for the discontinuation of therapy [4, 5].

Table 2: “Which health professional is mostly involved in MSmanagement?” (multiple answers possible).

Three months Twelve months𝑁 % 𝑁 %

Neurologist 253 96.56 239 96.37General doctor 90 34.35 83 33.46Nurse 77 29.38 65 26.20Physiotherapist 18 6.87 18 7.25Other 3 1.14 7 2.82Home assistant 1 0.38 0No one 1 0.38 3 1.20

Self-administration of DMDs and the notion that treat-mentwill help the patient to remain independent are themostimportant factors in determining the therapy choice (53.7%and 59.8% at 3 months and 53.9% and 52.3% at 12 months,resp.) (Table 5). These factors were more relevant in women(64.5%) with statistically significant difference (𝑃 = 0.03)compared to men (48.7%) at 3 months; the gender differencewas persistent, but not statistically significant at 12 months(men 41.7%, women 56.8%).

5. Conclusion

The World Health Organization indicates that patients ofdeveloped countries with chronic diseases exhibit a therapyadherence of only 50% (1) but assessing the adherence toDMDs in patients with MS is still an unsolved issue. At thepresent time, there are no reliablemarkers to verify the adher-ence to IFN𝛽 or glatiramer acetate treatment although bio-logical measurement in IFN𝛽 treated patients can identify asubset of nonadherent patients [18]. An indirect method maybe that of requesting patients to return empty vials to be


Table 3: “What is your main resource in coping with the illness?”


ParentsLow 82 31.29 86 34.67Medium 46 17.55 47 18.94High 134 51.13 115 46.36

The familyLow 21 8.00 37 14.91Medium 27 10.30 7 2.82High 214 81.67 204 82.35

Faith/religious beliefLow 108 41.22 88 35.47Medium 63 24.05 61 24.59High 91 34.73 99 39.91

FriendsLow 99 37.78 79 31.85Medium 76 28.99 73 29.33High 87 33.19 96 38.70

Support GroupsLow 202 77.09 172 69.35Medium 37 14.11 51 20.56High 23 8.77 25 10.07

Doctors/nursesLow 42 16.02 39 15.72Medium 44 16.78 54 21.77High 176 67.16 155 62.49

Hospital CenterLow 55 20.98 45 18.13Medium 39 15.26 50 20.15High 167 63.73 153 61.69

Table 4: “Who decided to start therapy?”

Three months𝑁 %

I decided 3 1.14I decided after discussing it with the neurologist 29 11.06I together with my neurologist 92 35.11My neurologist, even considering my opinion 75 28.62My neurologist 59 22.51ND 4 1.52(This question is only on the 3-month questionnaire).

counted, but even in this case there is no certainty whetherthe data may be accurate or not.The use of electronic deviceswith recording dose history certainly facilitates the task andprovides useful data on forgetfulness but does not exclude thepossibility of a voluntary nonadherence.

The overall level of adherence in previous studies waslower than that observed in our cohort [1–3, 7, 19]. In thestudy of Sabate [3] on 2314 patients with clinically isolatedsyndrome (CIS), about 40% of these patients discontinuedtheir first DMT during the observation period. In another

Table 5: Main factors in the choice of MSTherapy.


The drug’s mechanism ofaction

Low 36 13.9 25 10.4Medium 94 36.3 86 35.7High 129 49.8 130 53.9

The drug reduces therelapses

Low 22 8.5 14 5.8Medium 71 27.4 72 29.9High 166 64.1 155 64.3

The drug slows the diseaseprogression

Low 24 9.3 14 5.8Medium 61 23.6 69 28.6High 174 67.2 158 65.6

The drug produces fewerantibodies

Low 93 35.9 69 28.6Medium 125 48.3 134 55.6High 41 15.8 38 15.8

The drug is well knownLow 44 17.0 40 16.6Medium 113 43.6 102 42.3High 102 39.4 99 41.1

The drug has few sideeffects

Low 29 11.2 21 8.7Medium 97 37.5 112 46.5High 133 51.4 108 44.8

The drug improves the MRILow 61 23.6 36 14.9Medium 87 33.6 96 39.8High 111 42.9 109 45.2

The nurse support forinjections

Low 146 56.4 121 50.2Medium 63 24.3 82 34.0High 50 19.3 38 15.8

Information support of thecompany producing thedrug

Low 104 40.2 86 35.7Medium 104 40.2 113 46.9High 51 19.7 42 17.4

The intramuscular orsubcutaneous mode ofadministration

Low 55 21.2 47 19.5Medium 118 45.6 122 50.6High 86 33.2 72 29.9


Table 5: Continued.


The ability to let by myselfinjections

Low 41 15.8 27 11.2Medium 79 30.5 84 34.9High 139 53.7 130 53.9

The availability of anautoinjector

Low 70 27.0 42 17.4Medium 73 28.2 79 32.8High 116 44.8 120 49.8

How many times a weekshould I take the drug?

Low 49 18.9 35 14.5Medium 114 44.0 103 42.7High 96 37.1 103 42.7

The independence that atreatment can give

Low 33 12.7 28 11.6Medium 71 27.4 87 36.1High 155 59.8 126 52.3

Table 6: “How often is the medication taken according to neurolo-gist prescription?”


Always 255 97.32 233 93.95The dose is reduced 2 0.76 2 0.80The dose is increased 0 0.00 1 0.40The number of injections is reduced 2 0.76 6 2.41ND 3 1.14 6 2.41

study on 97 RRMS patients, Tremlett et al. [7] reported apercentage of 73% of DMDs missed doses, with 1 patient outof 10 having not taken more than 10 doses over a periodof 6 months. In this study, the most important factor formissing doses was the amount of alcohol consumed, whereasa low level of educations and the occurrence of relapses wereassociated with stopping the current DMDs in more than aquarter of the patients. These authors also found that the evi-dence of missed doses predicted future lack of adherence. Nocognitive or psychological test provided useful information.Treadaway et al. [19] used online questionnaires to analyze798 patients and reported nonadherence rates (missing oneor more injections within the last 4 weeks) ranging between36 and 39%.Themost common reason for missing injectionswas forgetfulness (58%). Other factors including injection-site reactions, quality of life, patients’ perceptions on theinjectable medications, hope, depression, satisfaction, andsupport were also assessed in relation to adherence, empha-sising the relevance of factors related to the injections

Table 7: Cause of change in the number or dosage of injections.

3 months 12 months𝑁 % 𝑁 %

Dosage inconvenient or difficult 2 1.7 1 0.9Forgot the administration 17 14.5 20 17.4The injection generated anxiety 14 12.0 15 13.0“I did not feel the need to do all injections” 1 0.8 3 2.6Tired of injections 11 9.4 9 7.8No one could do the injection 4 3.4 1 0.9Skin reactions 6 5.1 8 6.9Pain at the injection site 12 10.3 12 10.4Flu-like syndrome 12 10.3 5 4.3Depression 5 4.3 5 4.3Headache 3 2.6 5 4.3Fatigue 10 8.5 9 7.8Weakness 9 7.7 8 6.9“I did not get therapy” 3 2.6 1 0.9Not sure of the benefits 3 2.6 4 3.5Pregnant or plan to become pregnant 0 0.0 1 0.9More 5 4.3 8 6.9

Table 8: “Would you tell your neurologist you did not follow hisprescriptions?”

Three months Twelve months𝑁 % %M % F 𝑁 % %M % F

Yes 220 83,96 76.3 87.8 219 88,30 84.5 92.9No 40 15,26 23.7 12.2 24 9,67 15.5 7.1ND 2 0,76 5 2,01

procedure itself (site reactions, pain, anticipation anxiety, anddifficulty with administration route).

One of the most frequently reported causes of reducedadherence was the difficulty to accept injection therapy(via self-injection). Common reactions were fear, avoidance,anxiety, autonomic reactions, anddisgust. Somepatientswerehelped to inject the drug by familymembers but this behaviorcan decrease patient’s independence and the likelihood ofmissing injections if the designated family member is notavailable [20]. In addition to needle phobia, other reasons forskipping doses were the belief that injections are dangerous,that they remind of the status of being ill, and that they mayalter the physical aspect [21, 22]. Indeed, the belief that theprescribed therapy can be harmful and that it is a symbol ofthe disease may be important in altering the adherence evenwith oral therapies recently introduced in the treatment ofMS.

Our study was analysed in the first year of therapy andfocused only on adherence to the therapy as proper use ofthe drug (i.e., taking the medication at the right time anddose, on the right day). Previous studies [7, 23] alreadyfocused on the acceptance of therapy, allowing a predictionon the possible adherence mainly in the initial phase oftherapy. In subsequent periods, other factors such as the per-ception of the effectiveness of therapy may prevail [24] and


Table 9: “Forgotten, by choice or by accident, a few injections in thelast 4 weeks?” (∗).


Yes 37 14.12 40 16.12No 225 85.87 199 80.24ND — — 9 3.62(∗) “few” intended as 1 dose/month of interferon 𝛽1a-im, 1–3 doses/monthof other interferon or glatiramer acetates.

Table 10: “Decided to modify the prescribed dose in the last 4weeks?”


Yes 7 2.8 10 4.2No 244 97.2 227 95.8

assessments of adherence in the long term can be mainlyanalyzed retrospectively.

The percentage of adherence observed in our prospectivestudy (97.3% and 93.9% at 3 and 12 months) was higher thanthose previously reported (generally not greater than 70%).This finding is probably related to the active role played byhospital neurologists and nurses, who were directly involvedto share the decision of treatment initiation and substantiallycontributed to educate patients to properly administer thedrug, cope with adverse events, and plan the clinical follow-up. Meyniel et al. [4] report indeed discontinuation rates forDMDs greater in Canada (51.4%) and Australia (47.3%) thanin Italy (38.1%) or Spain (29.4%).

Our interpretation is supported by the response to thequestion “Decide to modify the prescribed dose in the last4 weeks?” (Table 10) with a negative response in 97.2% at 3months and 95.8% at 12 months but is partially weakened byanswer to the question “Would you tell your neurologist youdid not follow his prescriptions?” (Table 7), where 15.7% at 3months and 9.7% at 12 months claimed not to tell theirnonadherence to the neurologist. To the question “Have youforgotten, by choice or by accident, a few injections in the last4 weeks?” (Table 9), the 85.9% at 3 months and 80.2% at 12months of patients provide a negative response. To our opin-ion, these data underlie the intention of being adherent totherapy, despite a few doses missed, as this seemed to happenoccasionally and not deliberately (simple forgetfulness orother occasional factor).

Equally important was the analysis of interactions inthe starting therapy decision as a patient’s “active,” “passive,”or “collaborative” [20] participation in disease management(Table 4) might had an impact on adherence. Shared decisionmaking or shared opinion was the behavior of choice in 1/3 ofour patients, but is increasingly recognized as the ideal modelof patient-physician communication especially in chronicdiseases, such as MS, with partially effective treatments asMS.

MS centres are recognized to have a central role in MSmanagement. The growth of confidence in the referral neu-rologist is highlighted by Table 10 indicating the sincerity inreporting adherence to the therapy; a statistically significantdifference in the McNemar test with continuity correction(𝑃 = 0.048) is detected at 3 and 12 months.

A constant relationshipwith the center allows the patientsto follow a diagnostic and therapeutic process based onnational and international guidelines. The relevance of theneurologist stems clearly from our data, as the role of thegeneral practitioner is considered less important (33% versus96%) (Table 2). The central role in disease management andfidelity to the referral center are typical of MS managementin Italy where the clinical centers provide a total care of thepatient (diagnosis, clinical andpharmacologicalmanagementof symptoms and relapses, workup prescription,managementof side effects, referral to other specialists, interpretation ofresults, and management of intercurrent and extraneurolog-ical diseases). It is very likely that the intense involvement inpatient care by the center is the main motivation for the highpercentage of adherence that we observed.

Nurses specifically trained in the management of MSpatients are regarded as equally important (see Table 3) incoping with illness, in patient training, and in drug admin-istration management (50.3%) but not as “support for injec-tions” (Table 5).Themain resource to cope with the illness inthe first place consider the family as the most important, butdoctors, nurses, and the hospital are just after in the belief ofpatients.

A clear and focused doctor-patient relationship, aimedto control the appearance of “unrealistic optimistic expec-tations” [24], is important to maintain motivation and thusadherence in patients with MS. In addition, ongoing trainingand constant reinforcement of the value of treatment strate-gies are essential to maintain adherence to treatment.Although other factors such as cognitive [21] or psychiatricdisorders [13] may favor patients’ forgetfulness of drugadministration, positive reinforcement or other strategiesincluding a proper management of treatment expectationsshould be used to promote adherence, reinforce perceivedeffectiveness, and minimize adverse events [9, 21, 24].

Disclosure

Dr. Giancarlo Di Battista received speaker honoraria fromMerck Serono, Biogen Idec, Sanofi-Aventis and Bayer SheringPharma and received support for participation in Nationaland International Congresses from Bayer-Schering, Biogen-Idec, Merck Serono, Novartis, Sanofi-Aventis and Teva. Dr.Antonio Bertolotto received speaker honoraria from MerckSerono, Biogen Idec, Sanofi-Aventis, Bayer Shering Pharma.Dr. Claudio Gasperini received fee as speaker invited fromMerck Serono, Biogen Idec, Bayer Shering. Dr. AngeloGhezzi received honoraria for speaking fromBayer-Schering,Biogen-Idec, Merck-Serono, and Novartis, and for con-sultancy from Actelion, Merck-Serono, and Novartis, andreceived support for participation in National and Interna-tional Congresses from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, Sanofi-Aventis. Dr. Davide Maimone


received honoraria for speaking and travel grants fromBayer-Schering, Biogen Idec,Merck-Serono,Novartis, andTeva. Dr.Claudio Solaro received speaker honoraria from MerckSerono, Biogen Idec, Sanofi-Aventis, Bayer Shering Pharma.

Conflict of Interests

The authors declare that there is no conflict of interests.

Acknowledgments

The authors thank the Italian SNO (Societa dei Neurologi,Neurochirurghi e Neuroradiologi Ospedalieri) and BiogenIdec S.r.l. (Milan, Italy) which supported the SMART studyproviding research contract and organization services. Thefunding sources had no role in study design or conduct.Content of this paper is the sole responsibility of the authors.The authors thank the members of the SMART Study Groupwho provided the material necessary to conduct the studyincluding: Agostoni E., Balgera R. (A.O. Ospedale di Lecco,Lecco); Bartolini S., Ancona A. L. (Ospedale del Ceppo,Pistoia); Bertolotto A., Malentacchi M. (Azienda Ospeda-liero-Universitaria, San Luigi, Orbassano, TO); Cappellani A.(U.O. Neurologia-AUSL, Siracusa); Coniglio M. G. (A.O.Ospedale San Carlo, Potenza); Costantino G. (AziendaOspedaliero Universitaria, Foggia); Curatola L. (AziendaOspedaliero USL 12, S. Benedetto del Tronto, AP); Di BattistaG., Ferraro E. (A.C.O. San Filippo Neri, Roma); Dotta M.,L’Episcopo M. R. (Ospedale S. Lazzaro, Alba, CN); Fal-cini M. (Ospedale Misericordia e Dolce, Prato); Florio C.,Maniscalco G. (A.O.R.N. Cardarelli, Napoli); Gasperini C.,Ruggieri S. (A.O. San Camillo-Forlanini, Roma); Ghezzi A.,Baldini S. (A.O.S. Antonio Abate, Gallarate, VA); Guidi L.,Bartolozzi M. L. (Ospedale San Giuseppe, Empoli, FI);Guidotti M., Barrila C. (Ospedale Valduce, Como); GrimaldiL., Vitello G. (Fondazione Istituto San Raffaele-G. Giglio,Cefalu, PA); Iuliano G. (A.O. San Giovanni di Dio e R.D’Aragona, Salerno); Jandolo B., Galie E., andKoudriatseva T.(Istituti Fisioterapici Ospedalieri, Roma); Maddestra M.(Ospedale Civile Renzetti, Lanciano, CH); Maimone D.,Matta F., and Bianca M. (Azienda Ospedaliera Garibaldi,Nesima, Catania); Meucci G., Fioretti C. (Ospedale Civile,Livorno); Milone S. (Ospedali Riuniti Papardo-Piemonte,Messina); Neri W. (Ospedale G. B. Morgagni-L. Pierantoni,Forlı); Palumbo R. (A.O. Provincia di Lodi-Ospedale Mag-giore, Lodi); Perla F. (Ospedale Civile di Cuneo); Plewnia K.,Pieri S. (Ospedale Misericordia, Grosseto); Previdi P., Tot-tola M. (A.O.C. Poma, Mantova); Ragno M., Cacchio G.(Ospedale C. e G.Mazzoni ASL 13, Ascoli Piceno); Sabatini S.(Azienda Ospedaliera SantaMaria, Terni); Sinisi L., Mansi D.(Ospedale San Paolo-ASL NA1, Napoli); Solaro C. (OspedalePadre Antero Micone, Genova); Sosso L., Bucciantini E.(Ospedale Mauriziano, Torino); Spitalieri D. (A.O.R.N.S.Giuseppe Moscati, Avellino); Tartaglione A., Parodi S.(Ospedale S. Andrea-ASL 5, La Spezia).

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